Jack CR, Wengenack TM, Reyes DA, Garwood M, Curran GL, Borowski BJ, Lin J, Preboske GM, Holasek SS, Adriany G, Poduslo JF. In vivo magnetic resonance microimaging of individual amyloid plaques in Alzheimer's transgenic mice. J Neurosci. 2005 Oct 26;25(43):10041-8. PubMed.

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  1. This paper explores in-vivo MRI plaque number quantitation in PS1/APP doubly transgenic mice and relates these studies to invasive techniques such as ex-vivo MRI and histologic staining. The correlations observed between in-vivo MR plaque load and ex-vivo correlative measures are very encouraging. This study is at the cutting edge and represents the best state of the art for the field of MR amyloid imaging. The study was carefully performed by expert investigators who have extensively published in both MRI (in AD and mice) and histologic evaluation of the PS1/APP mouse.

    It is an important contribution to the literature, and great care has been taken to present the data in a balanced way. That is, the authors have pointed out the issues that remain to be surmounted before human amyloid imaging with MR is a possibility, and they note that a “number of significant technical barriers must be solved for this technique to be viable in the living human subject.”

    Of most importance is the issue of limiting motion to the degree necessary to resolve 100-micron plaques. It is interesting that with the present state of the art in MR imaging, it is no longer the resolution of the neuroimaging technique itself that is the limiting factor. Resolution of inanimate objects at 100 microns is no great feat in MR imaging studies today. The current challenge is to limit the inherent movement of living objects so this optimal resolution can be realized. While this paper and a similar previous report by this group (Jack et al., 2004) represent an impressive tour de force for cardiac and respiratory gating in order to minimize motion artifacts in the mice, it remains a great challenge to apply these approaches to humans. The authors put this work into a realistic context by stating, “This study serves as a foundation for using in-vivo MRI of transgenic mice (or other animal models) as a surrogate measure of plaque burden in natural history studies of plaque biology as well as drug discovery studies….” Regardless of when or if this MR technology is extended to humans, this remains a very important contribution for the animal work alone.

    Although each approach has its advantages, this MR approach is less invasive and measures a larger brain area than comparable multiphoton imaging studies that have demonstrated very high-resolution images of plaques in living mice (Bacskai et al., 2003). MicroPET studies, in addition to having lower resolution, have failed to show plaque detection in transgenic mice to this point [Klunk et al. (in press) and Toyama et al., 2005]. Thus, the latest findings by Jack et al. represent a significant advance in imaging plaques in animal models of AD and present the field with a worthy challenge to extend this technology to human studies.

    References:

    Jack CR, Garwood M, Wengenack TM, Borowski B, Curran GL, Lin J, Adriany G, Gröhn OH, Grimm R, Poduslo JF. In vivo visualization of Alzheimer's amyloid plaques by magnetic resonance imaging in transgenic mice without a contrast agent. Magn Reson Med. 2004 Dec;52(6):1263-71. PubMed.

    Bacskai BJ, Hickey GA, Skoch J, Kajdasz ST, Wang Y, Huang GF, Mathis CA, Klunk WE, Hyman BT. Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12462-7. PubMed.

    Toyama H, Ye D, Ichise M, Liow JS, Cai L, Jacobowitz D, Musachio JL, Hong J, Crescenzo M, Tipre D, Lu JQ, Zoghbi S, Vines DC, Seidel J, Katada K, Green MV, Pike VW, Cohen RM, Innis RB. PET imaging of brain with the beta-amyloid probe, [11C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer's disease. Eur J Nucl Med Mol Imaging. 2005 May;32(5):593-600. PubMed.

    View all comments by William Klunk

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